Imidazole derivatives and process for preparing the same

ABSTRACT

The invention relates to the imidazole derivatives as selective antagonistic substances against muscarinic acetylcholine and provides imidazole derivatives represented by a general formula (1) or (2) [wherein R1 is a phenyl group which may have substituent or thienyl group, R2 is a cyano group, a carboxyl group, CONR7R8 group (wherein R7 and R8 each independently represent hydrogen atom or lower alkyl group, or R7 and R8 may form a ring by alkylene chain which may contain hetero atom) or COOR9 group (wherein R9 is a lower alkyl group), R3 is a hydrogen atom or lower alkyl group, R4, R5 and R6 each independently represent hydrogen atom, lower alkyl group which may have substituent or cycloalkyl groups, or may form a condensed ring at the positions of R5 and R6 with benzene ring, R10 is a lower alkyl group or an aralkyl group which may have substituent, m is an integer from 1 to 6, and z is a halogen atom].

This application is a Division of application Ser. No. 08/652,551 Filedon Jun. 10, 1996, now U.S. Pat. No. 5,932,607, issued Aug. 3, 1999,which was filed as International Application No. PCT/JP94/02021 filedDec. 1, 1994.

TECHNICAL FIELD

The present invention relates to therapeutic agents, which are novelimidazole derivatives, and is particularly concerned to imidazolederivatives being anticholinergic agents, especially selectiveantagonists against muscarinic acetylcholine receptor, process forpreparing the same, and pharmaceutical compositions comprising them.

BACKGROUND TECHNOLOGIES

The anticholinergic agents exhibit anticonvulsant action andantisecretory action and have usefulness as the therapeutic agents forfunctional disorders of intestine, bladder, etc. At present, alkaloidssuch as atropine, aminoalkanol esters such as oxybutynin andpropantheline bromide, their quaternary ammonium salts and the like havebeen known as the anticholinergic agents, and they are blocking agentsfor muscarinic acetylcholine receptor. However, because of their poorselectivity among organs in the antagonistic action, the side effectsare caused and has posed problems. Therefore, the development of highlyselective anticholinergic drug is desired in clinic.

Though, there is a report on5-[1-(imidazole)methyl]-3,3-disubstituted-2(3H)-furanone derivatives asantagonists against muscarinic acetylcholine receptor, having imidazolegroup as a substituent, (Japanese Unexamined Patent Publication No. Hei4-103581), these compounds are different from the inventive compounds inthe structure, and yet they don't have adequate activity to satisfy.

The invention provides drugs having higher selectivity and more potentantagonistic activity on muscarinic acetylcholine receptor on smoothmuscle than muscarinic acetylcholine receptor on heart.

DISCLOSURE OF THE INVENTION

The inventors had focused on imidazole derivatives for the purposeaforementioned. As a result of diligent studies, so have found thatimidazole derivatives represented by the general formula (1) ##STR2##[wherein R₁ is a phenyl group which may have substituent or thienylgroup, R₂ is a cyano group; a carboxyl group; a CONR₇ R₈ group (whereinR₇ and R₈ each independently represent hydrogen atom or lower alkylgroup, or R₇ and R₈ may form a ring by alkylene chain which may containhetero atom) or a COOR₉ group (wherein R₉ is a lower alkyl group), R₃ isa hydrogen atom or a lower alkyl group, R₄, R₅ and R₆ each independentlyrepresent hydrogen atom, lower alkyl group which may have substituent orcycloalkyl groups, or may form a condensed ring at the positions of R₅and R₆ with benzene ring, and m is an integer from 1 to 6], or a generalformula (2) ##STR3## [wherein R₁ is a phenyl group which may havesubstituent or a thienyl group, R₂ is a cyano group, a carboxyl group, aCONR₇ R₈ group (wherein R₇ and R₈ each independently represent hydrogenatom or lower alkyl group, or R₇ and R₈ may form a ring by alkylenechain which may contain hetero atom) or COOR₉ group (wherein R₉ is alower alkyl group), R₃ is a hydrogen atom or a lower alkyl group, R₄, R₅and R₆ each independently represent hydrogen atom, lower alkyl groupwhich may have substituent or cycloalkyl group, or may form a condensedring at the positions of R₅ and R₆ with benzene ring, R₁₀ is a loweralkyl group or an aralkyl group which may have substituent, m is aninteger from 1 to 6, and z is a halogen atom],

have potent anticholinergic activity, especially selective and potentantagonistic activity on muscarine receptor of smooth muscles ofalimentary canal, trachea, bladder, etc., and have brought the inventionto completion.

By this reason, the inventive compounds are useful for the treatment ofmotility disorders of alimentary canal such as irritable bowel syndrome,diverticulum disease, functional diarrhea, esophageal achalasia andcardiospasm, treatment of biliary and urethral spasms, urinaryincontinence, etc, treatment of chronic respiratory obstructivediseases, and the like.

The term "substituents" applied to phenyl group shown in the inventionindicates halogen, lower alkyl group, lower alkoxy group, nitro group,phenyl group, etc. The term "halogens" indicate fluorine, chlorine,bromine and iodine.

For the "lower alkyl groups" indicate straight or branched chain withthe number of carbons from 1 to 6, such as methyl, ethyl and isopropyl.

The term "lower alkoxy groups" indicate ones with straight chain orbranched alkyl group with the number of carbons from 1 to 6 bonded tooxygen atom, such as methoxy group, ethoxy group and isopropoxy group.

The term "substituents of lower alkyl group" indicate halogen, loweralkoxy group, hydroxyl group, phenyl group, etc.

The term "cycloalkyl groups" indicate alicyclic hydrocarbons with thenumber of carbons from 3 to 8, such as cyclopropyl and cyclohexyl.

The term "aralkyl groups" indicate ones with straight chain or branchedalkylene group with the number of carbons from 1 to 6 bonded to phenylgroup which may have substituent, such as benzyl and phenylethyl.

The term "hetero atoms" indicate oxygen atom, sulfur atom and nitrogenatom.

In the invention, compounds represented by a general formula (3)##STR4## [wherein R₁, R₃, R₄, R₅, R₆ and m are as defined above],

may be prepared by reacting compounds represented by a general formula(4) ##STR5## [wherein, R₁, R₃ and m are as defined above, and X is aleaving group],

with compounds represented by a general formula (5) ##STR6## [whereinR₄, R₅ and R₆ are as defined above], preferably in the presence of base.

Here, the term "leaving group" indicate halogen, aliphatic sulfonyloxygroup such as methanesulfonyloxy group, arylsulfonyloxy group such astoluenesulfonyloxy group or the like.

The reaction can be carried out at 0 to 200° C., preferably at 60 to150° C. in an organic solvent such as dimethylformamide,N-methylpyrrolidone, N,N'-dimethylimidazolidinone, dimethyl sulfoxide orxylene in the presence of inorganic base such as sodium hydroxide,potassium hydroxide, calcium hydroxide, sodium carbonate or potassiumcarbonate or organic base such as triethylamine or pyridine.

Moreover, in the invention, compounds represented by a general formula(6) ##STR7## [wherein R₁, R₃, R₄, R₅, R₆, R₇, R₈ and m are as definedabove],

may be prepared by reacting compounds represented by a general formula(7) ##STR8## [wherein R₁, R₃, R₇, R₈ and m are as defined above, and Xis a leaving group],

with compounds represented by the general formula (5) ##STR9## [whereinR₄, R₅ and R₆ are as defined above], preferably in the presence of base.

The reaction can be carried out at 0 to 200° C., preferably at 60 to150° C. in an organic solvent such as dimethylformamide,N-methylpyrrolidone, N,N'-dimethylimidazolidinone, dimethyl sulfoxide orxylene in the presence of inorganic base such as alkali metal hydroxidesuch as sodium hydroxide or potassium hydroxide, metal carbonate such assodium carbonate or potassium carbonate or organic base such astriethylamine or pyridine.

Furthermore, in the invention, compounds represented by a generalformula (8) ##STR10## [wherein R₁, R₃, R₄, R₅, R₆ and m are as definedabove],

may be prepared by hydrolysis of compounds represented by the generalformula (3) ##STR11## [wherein R₁, R₃, R₄, R₅, R₆ and m are as definedabove].

The reaction may be carried out at 0 to 150° C., preferably at 100 to150° C. in a aqueous acidic solution of sulfuric acid or polyphosphoricacid and the like or aqueous alkaline solution of sodium hydroxide orpotassium hydroxide and the like.

Still more, in the invention, compounds represented by a general formula(9) ##STR12## [wherein R₁, R₃, R₄, R₅, R₆, R₉ and m are as definedabove],

can be prepared by alcoholysis of compounds represented by the generalformula (3) ##STR13## [wherein R₁, R₃, R₄, R₅, R₆ and m are as definedabove].

The reaction may be carried out at 0 to 150° C., preferably at 100 to150° C. in aqueous alcohol in the presence of inorganic acid such assulfuric acid or organic acid such as p-toluenesulfonic acid.

Still more, compounds represented by a general formula (10) ##STR14##[wherein R₁, R₃, R₄, R₅ R₆ and m are as defined above],

may be prepared by reacting compounds represented by a general formula(11) ##STR15## [wherein R₃, R₄, R₅, R₆ and m are as defined above, andR₁₁ is a lower alkyl group],

with compounds represented by a general formula (12)

    R.sub.1 --Y                                                (12)

[wherein R₁ is as defined above, and Y is lithium or magnesiumhalogenide],

under an inert gas.

The reaction may be carried out at -78 to 30° C. in anhydroustetrahydrofuran or ether.

Still more, compounds represented by the general formula (2) ##STR16##[wherein R₁, R₂, R₃, R₄, R₅, R₆ R₁₀ and m are as defined above, and Z isa halogen atom],

may be prepared by reacting compounds represented by the general formula(1) ##STR17## [wherein R₁, R₂, R₃, R₄, R₅, R₆ and m are as definedabove],

with compounds represented by a general formula (13)

    R.sub.10 --Z                                               (13)

[wherein R₁₀ and Z are as defined above],

The reaction can be carried out at 0 to 100° C. in an organic solventsuch as acetone, ethanol, acetonitrile or dimethylformamide.

In the case of the inventive imidazole derivatives containing one ormore asymmetric carbons, there will exist optical isomers. The inventionincludes these isomers and mixtures.

The novel compounds of the invention can be formed to acid additionsalts with pharmaceutically acceptable inorganic acids, for example,hydrochloric acid, sulfuric acid, hydrobromic acid and phosphoric acid,or organic acids, for example, maleic acid, fumaric acid, acetic acid,oxalic acid, tartaric acid, benzenesulfonic acid, and the like, byconventional methods.

The inventive novel compounds can be administered orally in the form oftablets, capsules, granules, powders, inhalants, syrups or the like, orcan be administrated by injections or suppositories or the like.

BEST EMBODIMENT FOR PUTTING THE INVENTION INTO PRACTICE

In following, the invention will be illustrated in detail based on theexamples.

Example 14-(2-Methyl-1-imidazolyl)-2,2-diphenylbutyronitrile.hydrochloride

4-Bromo-2,2-diphenylbutyronitrile (3.00 g, 10.0 mmol), 2-methylimidazole(2.46 g, 30.0 mmol), triethylamine (1.40 ml, 10.0 mmol) anddimethylformamide (50 ml) were mixed and stirred under heat for 30 hoursat 150° C. in a sealed tube. The solution was poured into water, and wasextracted with benzene. The organic extract was dried over anhydroussodium sulfate and then concentrated. The residue was purified by silicagel chromatography (elution solvent; dichloromethane:ethanol=10:1) andformed hydrochloric salt with hydrogen chloride-ether solution. Then,this was recrystallized from ethyl acetate to give 2.60 g of titlecompound as a colorless powder. Yield: 77%.

Melting point: 157-158.5° C.

Elemental analysis (%): As C₂₀ H₁₉ N₃.HCl.H₂ O. Calculated C: 67.50; H:6.23; N: 11.81. Observed C: 67.55; H: 6.21; N: 11.99.

¹ H-NMR (CDCl₃, δ), 7.35-7.42 (10H, m), 6.90 (1H, s), 6.77 (1H, s),3.90-3.94 (2H, m), 2.75-2.79 (2H, m), 2.25 (3H, s).

Examples 2 through 10

According to the process in Example 1, following compounds were prepared(Table 1).

                                      TABLE 1                                     __________________________________________________________________________      #STR18##                                                                       -                                                                                               Melting                                                          point(° C.)                                                      Ex-      (Boiling Composition Elemental analysis(%)                           ample R.sub.4 R.sub.5 R.sub.6 m Salt point) formula Calculated/analyzed     __________________________________________________________________________    2   C.sub.2 H.sub.5                                                                     H  H  1 HCl                                                                              140-141.5                                                                          C.sub.21 H.sub.21 N.sub.3.                                                           C:                                                                              70.95                                                                            H:                                                                              6.35                                                                             N:                                                                              11.82                                     HCl.1/5H.sub.2 O  70.80  6.45  11.98                                   3 i C.sub.3 H.sub.7 H H 1  (230) C.sub.22 H.sub.23 N.sub.3. C: 79.34 H:                                                  7.08 N: 12.62                            0.4 mmHg 1/5H.sub.2 O  79.47  7.04  11.57                               4 H H H 1 -- (220) C.sub.19 H.sub.17 N.sub.3. C: 78.43 H: 6.03 N: 14.44             0.4 mmHg 1/5H.sub.2 O  78.66  6.20  14.23                               5 H CH.sub.3 CH.sub.3 1 HCl 162-165 C.sub.21 H.sub.21 N.sub.3.HCl C:                                                     71.68 H: 6.30 N: 11.94                                                                  71.34  6.35  11.89     6   H     CH═CH                                                                           1 HCl                                                                              166-169                                                                            C.sub.23 H.sub.19 N.sub.3.                                                           C:                                                                              73.53                                                                            H:                                                                              5.42                                                                             N:                                                                              11.19                                CH═CH    HCl.1/10H.sub.2 O  73.44  5.57  11.16                        7   CH.sub.3                                                                            H  H  2    123-124                                                                            C.sub.21 H.sub.21 N.sub.3                                                            C:                                                                              79.97                                                                            H:                                                                              6.71                                                                             N:                                                                              13.32                                       80.09  6.78  13.15                                                   8 CH.sub.3 H H 3 HCl 166-167 C.sub.23 H.sub.23 N.sub.3. C: 70.48 H:                                                      6.72 N: 11.21                             HCl.1/2H.sub.2 O  70.19  6.64  11.09                                   9 c C.sub.3 H.sub.5 H H 1 -- (250) C.sub.22 H.sub.21 N.sub.3. C: 80.26                                                   H 6.49 N: 12.76                          0.7 mmHg 1/10H.sub.2 O  80.17  6.56  12.67                              10 CH.sub.3 O CH.sub.2 H H 1  124-125 C.sub.21 H.sub.21 N.sub.3 O C:                                                     76.11 H: 6.39 N: 12.68                                                                  76.11  6.40            __________________________________________________________________________                                                 12.29                        

Example 11 4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutylamide

4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutyronitrile (7.83 g, 26.0 mmol)and 70% sulfuric acid (50 ml) were mixed and stirred for 40 minutes at140 to 150° C. The solution was made alkaline and extracted with a mixedsolvent (5:1) of chloroform with ethanol. The organic extract was driedover anhydrous sodium sulfate and then concentrated. The residue wasrecrystallized from ethyl acetate-ethanol to give 2.02 g of titlecompound as colorless needle-like crystals. Yield: 32%

Melting point: 189-190° C.

Elemental analysis (%): As C₂₀ H₂₁ N₃ O. Calculated C: 75.21; H: 6.63;N: 13.16. Observed C: 74.98; H: 6.80; N: 13.00.

¹ H-NMR (CDCl₃, δ), 7.31-7.42 (10H, m), 6.85 (1H, s), 6.73 (1H, s), 5.49(1H, s), 5.33 (1H, s), 3.77-3.82 (2H, m), 2.69-2.74 (2H, m), 2.23 (3H,s).

Examples 12 through 20

According to the process in Example 11, following compounds wereprepared (Table 2).

                                      TABLE 2                                     __________________________________________________________________________      #STR19##                                                                       -                                                                          Ex-             Melting                                                                            Composition                                                                         Elemental analysis(%)                                ample R.sub.4 R.sub.5 R.sub.6 m point(° C.) formula Calculated/an                               alyzed                                             __________________________________________________________________________    12  C.sub.2 H.sub.5                                                                   H  H  1 144 146                                                                            C.sub.21 H.sub.23 N.sub.3 O                                                         C:                                                                              75.65                                                                            H:                                                                              6.95                                                                             N:                                                                              12.60                                            75.42  7.08  12.43                                                    13 n-C.sub.3 H.sub.7 H H 1 150-152 C.sub.22 H.sub.25 N.sub.3 O C: 76.05                                            H: 7.25 N: 12.09                                 75.98  7.25  12.03                                                    14 i-C.sub.3 H.sub.7 H H 1 176-178 C.sub.22 H.sub.25 N.sub.3 O. C:                                                 75.66 H: 7.27 N: 12.03                         1/10H.sub.2 O  75.67  7.30  12.04                                       15 H H H 1 172-175 C.sub.19 H.sub.19 N.sub.3 O. C: 72.17 H: 6.44 N:                                                13.29                                          3/5H.sub.2 O  72.20  6.32  12.89                                      16  H   CH--CH                                                                              1 197 199                                                                            C.sub.23 H.sub.21 N.sub.3 O.                                                        C:                                                                              75.80                                                                            H:                                                                              6.08                                                                             N:                                                                              11.53                                      CH--CH   1/5H.sub.2 O  75.90  5.95  11.27                                 17  H   CH.sub.3                                                                         CH.sub.3                                                                         1 163  C.sub.21 H.sub.23 N.sub.3 O                                                         C:                                                                              75.65                                                                            H:                                                                              6.95                                                                             N:                                                                              12.60                                         164.5   75.37  7.05  12.43                                               18 H C.sub.2 H.sub.5 C.sub.2 H.sub.5 1 194-196 C.sub.23 H.sub.27                                                   N.sub.3 O C: 76.42 H: 7.53 N:                                                 11.62                                            76.25  7.64  11.48                                                    19 CH.sub.3 H H 3 154-156 C.sub.22 H.sub.25 N.sub.3 O C: 76.05 H: 7.25                                             N: 12.09                                         75.96  7.22  11.93                                                    20 t-C.sub.4 H.sub.9 H H 1 136-138 C.sub.23 H.sub.27 N.sub.3 O. C:                                                 74.56 H: 7.62 N: 11.34                         1/2H.sub.2 O  74.60  7.46  11.10                                      __________________________________________________________________________

Example 214-(2-Isopropyl-3-methyl-1-imidazolyl)-2,2-diphenylbutylamide.iodide

A mixture of 4-(2-isopropyl-1-imidazolyl)-2,2-diphenylbutylamide (250mg, 0.720 mmol), methyl iodide (5.0 ml), acetone (100 ml) and ethanol(1.0 ml) was stirred under heat for 10 hours in a sealed tube. After thesolution was concentrated, the residue was recrystallized from ethylacetate-ethanol to give 0.35 g of title compound as pale yellowneedle-like crystals. Yield: 99%

Melting point: 238-239° C.

Elemental analysis (%): As C₂₃ H₂₈ IN₃ O. Calculated C: 56.45; H: 5.77;N: 8.59. Observed C; 56.35; H: 5.64; N: 8.73.

¹ H-NMR (d₆ -DMSO, δ), 7.64 (1H, s), 7.61 (1H, s), 7.46 (1H, s),7.31-7.43 (10H, m), 6.88 (1H, s), 3.81-3.88 (5H, m), 3.24-3.30 (1H, m),2.73-2.78 (2H, m), 1.16 (6H, d, J=7.3Hz).

Examples 22 through 26

According to the process in Example 21, following compounds weresynthesized (Table 3).

                                      TABLE 3                                     __________________________________________________________________________      #STR20##                                                                       -                                                                          Ex-                  Melting                                                                            Composition                                                                          Elemental analysis(%)                          ample R.sub.4 R.sub.10 m z point(° C.) formula Calculated/analyze                                     d                                            __________________________________________________________________________    22  CH.sub.3                                                                          CH.sub.3 1 1 234-236                                                                            C.sub.21 H.sub.24 IN.sub.3 O.                                                        C:                                                                              54.25                                                                            H:                                                                              5.29                                                                             N:                                                                              9.04                                     1/5H.sub.2 O  54.02  5.30  9.00                                         23 CH.sub.3 C.sub.2 H.sub.5 1 1 189-192 C.sub.22 H.sub.26 IN.sub.3 O.                                                    C: 54.35 H: 5.64 N: 8.64                                                             3/5H.sub.2 O  54.54                                                    5.78  8.34                          - 24 CH.sub.3                                                                                                             1 Br 230 232 C.sub.27                                                       H.sub.28 BrN.sub.3 O C:                                                       66.12   66.41 H: 5.75   5.86                                                  N: 8.57   8.68                      - 25 C.sub.2 H.sub.5 CH.sub.3 1 1 229-  230.5 C.sub.22 H.sub.26                                                         IN.sub.3 O C: 55.59   55.32                                                   H: 5.51   5.51 N: 8.84                                                        8.94                                - 26 n C.sub.3 H.sub.7 CH.sub.3 1 1 215 216 C.sub.23 H.sub.28 IN.sub.3                                                  O C: 56.45   56.69 H: 5.77                                                    5.83 N: 8.59   8.89              __________________________________________________________________________

Example 27 3-(2-Methyl-1-imidazolyl)-1,1-diphenylpropanol

In a 200 ml two-neck flask, under an atmosphere of argon, a solution ofethyl 3-(2-methyl-1-imidazolyl)propionate (3.37 g, 18.5 mmol) inanhydrous tetrahydrofuran was added to 50 ml of 1.8M phenyllithiumsolution at 0° C. After stirred for 3.5 hours at 10° C., the mixture wasallowed to stand overnight at room temperature. The solution was pouredinto water, which was extracted with ethyl acetate. The organic extractwas washed with saturated saline solution and dried over anhydroussodium sulfate, followed by concentration. The residue was purified bysilica gel chromatography (elution solvent; ethyl acetate-ethanol=10:1)and then recrystallized from n-hexane-ethyl acetate. This was furtherrecrystallized from ethanol-benzene to give 320 mg of title compound aswhite needle-like crystals. Yield: 6%

Melting point: 212-214° C.

Elemental analysis (%): As C₁₉ H₂₀ N₂ O1/10H₂ O. Calculated C: 77.57; H:6.92; N: 9.52. Observed C: 77.66; H: 6.87; N: 9.24.

¹ H-NMR (CDCl₃, δ), 7.22-7.44 (10H, m), 6.80 (1H, s), 6.72 (1H, 2),3.79-3.84 (2H, m), 2.90 (1H, brs), 2.64-2.69 (2H, m), 2.18 (3H, s).

Example 28 3-(2-Methyl-1-imidazolyl)-1,1-diphenylbutanol

Similarly to Example 24, except that 3.60 g (18.3 mmol) of ethyl3-(2-methyl-1-imidazolyl)butyrate was used in place of ethyl3-(2-methyl-1-imidazolyl)propionate, 600 mg of title compound wereobtained as white cyrstals. Yield: 11%

Melting point: 168-169° C.

Elemental analysis (%): As C₂₀ H₂₂ N₂ O1/5H₂ O. Calculated C: 77.49; H:7.28; N: 9.04. Observed C: 77.21; H: 7.18; N: 8.90.

¹ H-NMR (CDCl₃, δ), 7.19-7.42 (10H, m), 6.87 (1H, d, J=2.0Hz), 6.85 (1H,s), 4.25 (1H, sextet, J=6.2Hz), 2.75 (2H, d, J=5.9Hz), 2.52 (1H, brs),2.00 (3H, s), 1.34 (3H, d, J=6.9Hz).

Example 29

According to the process in Example 1, following compound wassynthesized (Table 4).

                                      TABLE 4                                     __________________________________________________________________________      #STR22##                                                                       -                                                                                               Melting                                                          point(° C.)                                                      Ex-      (Boiling Composition Elemental analysis(%)                           ample R.sub.1 R.sub.4 R.sub.5 R.sub.6 m point) formula Calculated/analyz                                    ed                                            __________________________________________________________________________      27                                                                                                                        CHTR23##                                                                    .sub.3 H H 1 (240)  0.8 mmHg                                                  C.sub.20 H.sub.17 F.sub.2                                                     N.sub.3.  1/20H.sub.2 O C:                                                    71.01   71.39 H: 5.10   5.50                                                  N: 12.42   12.35                  __________________________________________________________________________

Examples 30 through 33

According to the process in Example 11, following compounds weresynthesized (Table 5).

                                      TABLE 5                                     __________________________________________________________________________      #STR24##                                                                       -                                                                          Ex-                         Melting                                                                            Composition                                                                          Elemental analysis                      ample R.sub.1 R.sub.3 R.sub.4 R.sub.5 R.sub.6 m point(° C.)                                                  formula Calculated/analyzed           __________________________________________________________________________      30                                                                                                                                H CH25##                                                                    .sub.3 H H 1 206-                                                             207.5 C.sub.20                                                                H.sub.19 F.sub.2                                                              N.sub.3 O C: 67.59                                                            67.23 H: 5.39   5.55                                                          N: 11.82   11.63                                                                - 31                                                                          H H n C.sub.3                                                               H.sub.7 n C.sub.3                                                             H.sub.7 1 147  148                                                            C.sub.25 H.sub.31                                                             N.sub.3 O.  1/5H.sub.2                                                         O C: 76.38   76.28                                                           H: 8.05   7.79 N:                                                             10.69   10.69                                                                   - 32                                                                          H CH.sub.3 H H 4                                                            159-  151 C.sub.23                                                            H.sub.27 N.sub.3 O C:                                                         76.42   76.29 H: 7.53                                                           7.53 N: 11.62                                                               11.55                        - 33                                                                                                                             CH.sub.3 CH.sub.3 H                                                         H 1 148  150 C.sub.21                                                         H.sub.23 N.sub.3 O C:                                                         75.65   75.48 H: 6.95                                                           7.16 N: 12.60                                                               12.50                     __________________________________________________________________________

Examples 34 through 53

According to the process in Example 21, following compounds weresynthesized (Table 6, Table 7).

                                      TABLE 6                                     __________________________________________________________________________      #STR29##                                                                       -                                                                          Ex-                    Melting                                                                            Composition                                                                           Elemental analysis                          ample R.sub.4 R.sub.10 m z point(° C.) formula Calculated/analyze                                        d                                         __________________________________________________________________________      34 CH.sub.3 n-C.sub.3 H.sub.7 1 1 173 C.sub.23 H.sub.28 IN.sub.3 O. C:                                                      56.04 H: 5.81 N: 8.52                                                               175 1/5H.sub.2 O                                                        55.89  5.68  8.51                                                              35 CH.sub.3 n-C.sub.4                                                        H.sub.9 1 1 164 C.sub.24                                                      H.sub.30 IN.sub.3 O C:                                                        57.26 H: 6.01 N: 8.35                                                               166   57.08  5.94                                                       8.23                             - 36 CH.sub.3                                                                                                                1 Br 198-  199 C.sub.27                                                     H.sub.27 BrClN.sub.3 O.                                                       1/5H.sub.2 O C: 61.36                                                         61.16 H: 5.23   5.08 N:                                                       7.95   7.91                      - 37 CH.sub.3                                                                                                                1 Br 221-  222 C.sub.27                                                     H.sub.27 BrClN.sub.3 O C:                                                     61.78   61.54 H: 5.19                                                         5.32 N: 8.01   7.95                                                             - 38 CH.sub.3                                                                 1 Br 133-  135 C.sub.27                                                     H.sub.27 BrClN.sub.3 O.                                                       1/2H.sub.2 O C: 60.74                                                         60.78 H: 5.29   5.31 N:                                                       7.87   7.41                      - 39 CH.sub.3                                                                                                                1 Br 224-  226 C.sub.28                                                     H.sub.30 BrN.sub.3 O.                                                         3/10H.sub.2 O C: 65.96                                                        66.01 H: 6.05   5.96 N:                                                       8.24   8.17                      - 40 CH.sub.3                                                                                                                1 Br 210-  212 C.sub.28                                                     H.sub.30 BrN.sub.3 O.                                                         3/10H.sub.2 O C: 65.96                                                        65.81 H: 6.05   5.97 N:                                                       8.24   8.02                      - 41 CH.sub.3                                                                                                                1 Br 240-  242 C.sub.28                                                     H.sub.30 BrN.sub.3 O.                                                         3/10H.sub.2 O C: 65.96                                                        66.00 H: 6.05   6.09 N:                                                       8.24   8.28                      - 42 CH.sub.3                                                                                                                1 Br 205-  206 C.sub.27                                                     H.sub.27 Br.sub.2 N.sub.3                                                     O C: 56.96   56.74 H:                                                         4.78   4.91 N: 7.38                                                           7.60                             - 43 CH.sub.3                                                                                                                1 Br 219-  221 C.sub.27                                                     H.sub.27 Br.sub.2 N.sub.3                                                     O.  3/5i-Pr()H C: 57.14                                                       56.88 H: 5.29   5.50 N:                                                       6.94   6.71                   __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________    Ex-                        Melting                                                                            Composition                                                                           Elemental analysis                      ample R.sub.4 R.sub.10 m z point(° C.) formula Calculated/analyze                                            d                                     __________________________________________________________________________      44 CH.sub.3                                                                                                                       1 Br 139-  141                                                              C.sub.27 H.sub.26                                                             F.sub.2 BrN.sub.3 O.                                                          1/2EtOH C: 61:21                                                              61.34 H: 5.32   5.52                                                          N: 7.65   7.38                                                                  - 45 CH.sub.3                                                                 1 Br 206  208                                                               C.sub.27 H.sub.26                                                             F.sub.2 BrN.sub.3 O                                                           C: 61.60   61.72 H:                                                           4.98   5.14 N: 7.98                                                           7.96                         - 46 CH.sub.3                                                                                                                    1 Br 225  262                                                               C.sub.27 H.sub.26                                                             F.sub.2 BrN.sub.3 O                                                           C: 61.60   61.38 H:                                                           4.98   5.05 N: 7.98                                                           7.91                         - 47 CH.sub.3                                                                                                                    1 Br 215  217                                                               C.sub.27 H.sub.26                                                             F.sub.2 BrN.sub.3 O                                                           C: 61.60   61.40 H:                                                           4.98   5.27 N: 7.98                                                           7.79                         - 48 CH.sub.3                                                                                                                    1 Br 273  275                                                               C.sub.27 H.sub.26                                                             BrCl.sub.2 N.sub.3 O                                                          C: 57.98   57.91 H:                                                           4.69   4.75 N: 7.51                                                           7.74                         - 49 CH.sub.3                                                                                                                    1 Br 215  217                                                               C.sub.27 H.sub.27                                                             BrN.sub.4 O.sub.3 C:                                                          60.57   60.56 H: 5.08                                                           5.19 N: 10.46                                                               10.34                        - 50 CH.sub.3                                                                                                                    1 Cl 248-  249                                                              C.sub.33 H.sub.32                                                             ClN.sub.3 O C: 75.92                                                           75.54 H: 6.18   6.37                                                         N: 8.05   7.92                                                                  - 51 CH.sub.3                                                                 3 Br 155-  157                                                              C.sub.29 H.sub.32                                                             BrN.sub.3 O.                                                                  1/10H.sub.2 O C:                                                              65.96   66.76 H: 6.24                                                           6.21 N: 8.08   7.97        - 52 CH.sub.3                                                                                                                    3 Br 205-  207                                                              C.sub.29 H.sub.31                                                             BrClN.sub.3 O C:                                                              62.38   62.21 H: 5.70                                                           5.90 N: 7.53   7.24        - 53 CH.sub.3                                                                                                                    2 Br 171-  173                                                              C.sub.28 H.sub.30                                                             BrN.sub.3 O.                                                                  1/2H.sub.2 O C: 65.50                                                           65.37 H: 6.09                                                               6.02 N: 8.18              __________________________________________________________________________                                                        8.30                  

Experimental Example

1. Anticholinergic Action in Guinea-pig Ileum and Atria

Male Hartley guinea pigs were sacrificed by blowing on the head andbleeding.

Ileal segments (about 3 cm long) were suspended in organ bathscontaining Tyrode solution equilibrated with a mixture of 95% O₂ and 5%CO₂ at 32° C.

Responses to acetylchloline (ACh) added cumulatively to the baths wereisotonically recorded under a tension of 1 g. Dose-response curves ofACh were determined in the absence and presence of test compounds invarious concentrations added to the baths 5 min. before ACh application.

The affinity (pA₂) of test compounds for muscarinic receptor wasdetermined according to Schild method (Arunlakshana, O. and Schild, H.O. (1959) Brit. J. Pharmacol., 14 48-58).

The isolated atria were suspended under 0.5 g tension in organ bathscontaining Tyrode solution gassed with 95% O₂ and 5% CO₂ at 32° C.

Dose-response curves were obtained by cumulative addition of ACh andrepeated in the presence of various concentrations of test compounds,allowing 10 min. equilibration time.

The affinity of test compounds were determined as described for ileum.Results are shown in Table 8.

                  TABLE 8                                                         ______________________________________                                                         Anticholinergic                                                No. of        activity (pA.sub.2)                                           examples         Ileum   Atrium                                               ______________________________________                                         7               8.95    8.21                                                    8       8.17       7.08                                                      11    10.16     8.88                                                          14      9.17     7.73                                                         Atropine      8.67      8.91                                                  Oxybutynin     8.44      8.39                                               ______________________________________                                    

The compounds of the present invention had a high affinity formuscarinic receptors in guinia pig ileum but a much lower affinity forcardiac receptors.

In particular, the affinities obtained for compounds of Example 8, 11and 14 were 10 times greater for receptors in ileum as compared toreceptors in heart.

2. Effect on Rhythmic Bladder Contraction

Male Wistar rats were fixed in supine position under the halothaneanesthesia and a balloon-tip catheter was inserted into the bladderthrough the small incision of apex opening a lower abdomen along themidline, followed by purse-string suture. The catheter was led out ofupper end of abdominal incision sutured, connected with a pressuretransducer.

The balloon was filled with about 0.1 to 0.3 ml of water. After therhythmic contraction of the urinary bladder became constant at athreshold intravesical pressure, test compounds were givenintraduodenally. The inhibitory effects were estimated by the reductionin amplitude of bladder contraction. The compounds of the presentinvention decreased in amplitude of bladder contraction at a dose of0.03 mg/kg or more.

3. Effect on bethanechol-induced diarrhea

Test compounds were administered orally to male ICR mice and, 30 min.later 20 mg/kg of bethanechol were given subcutaneously. The appearanceof diarrhea was observed from the administration of bethanechol until0.5 hours later.

The compounds of the present invention show the inhibitory effects of adose of 0.06 mg/kg or more.

4. Anticholinergic Action in Guinea-pig Trachea

Male Hartley guinea-pigs were killed by blowing on the head andbleeding.

Ring strips of trachea were suspended in organ bath filled with Tyrodesolution, kept at 37° C. and gassed with a mixture of 95% O₂ and 5% CO₂.

Responses to ACh were isometrically recorded under a tension of 1 g.Concentration-Response curves were obtained cumulative addition of AChand repeated in the presence of various concentrations of testcompounds, allowing 10 minutes equilibration time.

The affinity (pA₂) of test compounds for muscarinic receptor wasdetermined according to Schild method (Arunlakshana, O. and Schild, H.O. (1959), Brit. J. Pharmacol., 14 48-58) or van Rossum (van Rossum, J.M. (1963), Arch. Int. Pharmacodyn, Ther., 143 299-330). Results areshown in Table 9.

                  TABLE 9                                                         ______________________________________                                                         Anticholinergic                                                No. of           activity (pA.sub.2)                                        examples         Trachea Atrium                                               ______________________________________                                        44               8.28    7.54                                                   50         8.34     7.52                                                      51       8.34      7.70                                                       Ipratropium    8.85     8.82                                                ______________________________________                                    

The affinities (pA₂) of the compounds of the present invention weresignificantly greater for muscarinic receptors in trachea as compared toreceptors in heart.

Utilizability in the Industry

As descried above, the compounds of the present invention will beclinically useful in treating irritable bowel syndrome, dysuria such aspollakiuria and urinary incontinence and chronic respiratory obstructivediseases.

We claim:
 1. An imidazole represented by formula (2) ##STR48## whereinR₁ is a phenyl group which may be optionally substituted with one ormore substituents selected from the group consisting of halogen, loweralkyl group, lower alkoxy group, nitro group, and phenyl group, R₂ is acarboxyl group or CONR₇ R₈ group wherein R₇ and R₈ are eachindependently hydrogen atoms or lower alkyl groups, R₃ is a hydrogenatom or a lower alkyl group, R₄, R₅ and R₆ are each independentlyhydrogen atoms, lower alkyl groups which may be independently optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkoxy group, hydroxy group, and phenylgroup, or C₃ -C₈ cycloalkyl groups, R₁₀ is a lower alkyl group or anaralkyl group which may be optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkylgroup, lower alkoxy group, hydroxyl group, nitro group and phenyl group,and m denotes an integer from 1 to 6 and Z is a halogen atom.
 2. Apharmaceutical composition, comprising:an imidazole represented byformula (2) ##STR49## wherein R₁ is a phenyl group which may beoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl group, lower alkoxy group,nitro group, and phenyl group, R₂ is a carboxyl group or CONR₇ R₈ groupwherein R₇ and R₈ are each independently hydrogen atoms or lower alkylgroups, R₃ is a hydrogen atom or a lower alkyl group, R₄, R₅ and R₆ areeach independently hydrogen atoms, lower alkyl groups which may beindependently optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkoxy group,hydroxy group, and phenyl group, or C₃ -C₈ cycloalkyl groups, R₁₀ is alower alkyl group or an aralkyl group which may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl group, lower alkoxy group, hydroxylgroup, nitro group and phenyl group, and m denotes an integer from 1 to6 and Z is a halogen atom, and an inert carrier.
 3. A method fortreating dysuria comprising:administering, to a subject in need thereof,an effective amount of a composition comprising:an imidazole representedby formula (2) ##STR50## wherein R₁ is a phenyl group which may beoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl group, lower alkoxy group,nitro group, and phenyl group, R₂ is a carboxyl group or CONR₇ R₈ groupwherein R₇ and R₈ are each independently hydrogen atoms or lower alkylgroups, R₃ is a hydrogen atom or a lower alkyl group, R₄, R₅ and R₆ areeach independently hydrogen atoms, lower alkyl groups which may beindependently optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkoxy group,hydroxy group, and phenyl group, or C₃ -C₈ cycloalkyl groups, R₁₀ is alower alkyl group or an aralkyl group which may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl group, lower alkoxy group, hydroxylgroup, nitro group and phenyl group, and m denotes an integer from 1 to6 and Z is a halogen atom, and an inert carrier.